The objective of this research is to elucidate the genes, cells, and mechanisms involved in the regulation of natural cell-mediated cytotoxicity (NCMC). A series of mutations in mice have been identified that affect natural killer (NK) cells including motheaten (absent), hairless, beige, obese and steel-steel dickie (reduced), and nude and lymphoproliferation (elevated). The sites of gene action of several of these mutants will be examined in detail using mediator, target binding and cytotoxic cell frequency, and cytotoxic precursor cell assays. The relationship between autoimmune disease and NK cell dysfunction will be examined. The activation of NK cells by allowantigents or by SM/J-associated genes will be studied. The specificity of NK cell activity and the conversion of NK resistant lines to a susceptible phenotype will be studied using a non-human primate model.